L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Recovery course of persistent posterior subretinal fluid after successful repair of rhegmatogenous retinal detachment.

PURPOSE: To investigate best corrected visual acuity (BCVA), subretinal fluid (SRF) absorption time or ellipsoid zone (EZ) restoration time and various variables in patients with persistent SRF after successful primary repair of rhegmatogenous retinal detachment (RRD). METHODS: This retrospective multicenter study allowed independent analysis of the healing pattern by two observers based on composite of serial cross-sectional macular optical coherence tomography (OCT) scans. Univariate and multivariate analyses were implemented. RESULTS: One hundred and three cases had persistent SRF after pars plana vitrectomy, scleral buckling, or pneumatic retinopexy. By univariate analysis, SRF resolution time correlated positively with the number of retinal breaks (p < 0.001) and with increased myopia (p = 0.011). Using multivariate analysis, final BCVA (log MAR) correlated positively with age, duration of RRD, initial BCVA (OR = 3.28; [95%CI = 1.44-7.47]; p = 0.015), and SRF resolution time (OR = 0.46 [95%CI 0.21-1.05]; p = 0.049). EZ restoration time was longer with increasing number of retinal tears (OR = 0.67; [95%CI 0.29-1.52]; p = 0.030), worse final BCVA, and presence of macula-off RRD (OR = 0.26; [95%CI 0.08-0.88]; p = 0.056). SRF resolution time correlated marginally with prone position. CONCLUSIONS: Residual posterior SRF is more common in eyes with multiple breaks or in myopic eyes. Final BCVA is better in younger subjects and in eyes with shorter duration of RRD. Persistent SRF is a self-limited disorder with a mean resolution of 11.2 months with good visual prognosis improving from a mean baseline logMAR of 1.08 to 0.25 at one year.

High quality de novo genome assembly of the non-conventional yeast Kazachstania bulderi describes a potential low pH production host for biorefineries.

Kazachstania bulderi is a non-conventional yeast species able to grow efficiently on glucose and δ-gluconolactone at low pH. These unique traits make K. bulderi an ideal candidate for use in sustainable biotechnology processes including low pH fermentations and the production of green chemicals including organic acids. To accelerate strain development with this species, detailed information of its genetics is needed. Here, by employing long read sequencing we report a high-quality phased genome assembly for three strains of K. bulderi species, including the type strain. The sequences were assembled into 12 chromosomes with a total length of 14 Mb, and the genome was fully annotated at structural and functional levels, including allelic and structural variants, ribosomal array and mating type locus. This high-quality reference genome provides a resource to advance our fundamental knowledge of biotechnologically relevant non-conventional yeasts and to support the development of genetic tools for manipulating such strains towards their use as production hosts in biotechnological processes.

The significant IgG4 infiltrate in autoimmune hepatitis is associated with a greater ductular reaction and more advanced liver disease.

BACKGROUND: Sclerosing cholangitis is the typical IgG4-related disease digestive involvement. However, the role of the IgG4 liver expression in autoimmune hepatitis remains unknown. AIMS: to assess whether the expression of IgG4 plasma cells in patients with autoimmune hepatitis (AIH) was associated with different outcomes. METHODS: Retrospective study including patients diagnosed with AIH by biopsy from January-2009 to June-2021. At least mild IgG4 expression (>10 IgG4+-plasma cells per field) was considered as significant. RESULTS: 85 patients with AIH were included. Overall, 58.8% were women, mean age 54 years. Nine (10.6%) presented cirrhosis at diagnosis. Fifteen (17.6%) had significant IgG4 liver expression. Patients with IgG4 infiltrate were older (p = 0.021), presented liver cirrhosis more frequently (33.3% vs. 5.7%, p = 0.007), greater IgG plasma values (p = 0.008) and atypical ANCAs (p = 0.086); ductular reaction was also more common (p = 0.009). Complete remission rate was similar regardless of the IgG4 infiltrate. Time to corticosteroids discontinuation was longer in subjects with IgG4 infiltrate (p = 0.068), but second-line therapy tended to be less frequent (p = 0.187). CONCLUSION: Significant IgG4 liver infiltrate in patients with autoimmune hepatitis is associated with more advanced liver disease. The greater ductular reaction mediated by the IgG4 infiltrate may be the cause for this finding, though this finding should be prospectively assessed.

mTOR inhibitors a potential predisposing factor for chronic hepatitis E: Results from the prospective collaborative CHES study (Chronic Hepatitis EScreening in patients with immune impairment and increased transaminases levels).

BACKGROUND: Chronic hepatitis E virus (HEV) in persons with immune impairment has a progressive course leading to a rapid progression to liver cirrhosis. However, prospective data on chronic HEV is scarce. The aim of this study was to determine the prevalence and risk factors for chronic HEV infection in subjects with immune dysfunction and elevated liver enzymes. PATIENTS AND METHODS: CHES is a multicenter prospective study that included adults with elevated transaminases values for at least 6 months and any of these conditions: transplant recipients, HIV infection, haemodialysis, liver cirrhosis, and immunosuppressant therapy. Anti-HEV IgG/IgM (Wantai ELISA) and HEV-RNA by an automated highly sensitive assay (Roche diagnostics) were performed in all subjects. In addition, all participants answered an epidemiological survey. RESULTS: Three hundred and eighty-one patients were included: 131 transplant recipients, 115 cirrhosis, 51 HIV-infected subjects, 87 on immunosuppressants, 4 hemodialysis. Overall, 210 subjects were on immunosuppressants. Anti-HEV IgG was found in 94 (25.6%) subjects with similar rates regardless of the cause for immune impairment. HEV-RNA was positive in 6 (1.6%), all of them transplant recipients, yielding a rate of chronic HEV of 5.8% among solid-organ recipients. In the transplant population, only therapy with mTOR inhibitors was independently associated with risk of chronic HEV, whereas also ALT values impacted in the general model. CONCLUSIONS: Despite previous abnormal transaminases values, chronic HEV was only observed among solid-organ recipients. In this population, the rate of chronic HEV was 5.8% and only therapy with mTOR inhibitors was independently associated with chronic hepatitis E.

Development of an algorithm for IgG4-related disease management.

OBJECTIVES: IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory condition affecting multiple organs lacking standardized management. In this article, we review the evidence available to provide European expert-based statements on the management of IgG4-RD which were integrated in a final algorithm. METHODS: A panel of nine European experts in IgG4-RD from different specialties was asked to elaborate a set of consensus statements through a Delphi exercise. Three rounds of survey were taken. Consensus was reached when ≥75% of the responders agreed with a statement. RESULTS: Thirty-one statements on induction treatment, maintenance treatment, non-pharmacological treatment, and general considerations were assessed. Patients should be treated promptly in situations when there is an immediate organ threatened, or when organ damage is anticipated. Glucocorticoids (GC) are considered the first line of treatment and should be progressively tapered. Maintenance treatment is recommended for patients with high disease activity or with risk factors for relapse. Rituximab is effective for induction and maintenance of remission, but its use can be limited by economics. Low dose GC with or without GC-sparing agents can be used for maintenance therapy. Stenting or surgery should be ancillary to pharmacological treatment. Follow up should be based on physical examination, blood works, and imaging studies. Furthermore, it should be tailored on individual patient clinical history. 18-fluorodeoxyglucose positron emission tomography/computerized tomography may provide additional information over other imaging modalities. CONCLUSIONS: These new statements and algorithm reached a high degree of agreement and may help guiding the clinical management of IgG4-RD.

Co Treatment With Biologic Agents and Immunotherapy in the Setting of irAEs of Difficult Management.

In recent years, immunotherapy has become an important pillar of cancer treatment, with high response rates regardless of tumor histology or baseline mutations, sometime in patients without any alternative of treatment. Moreover, these treatments are moving from later line therapies to front-line therapies in the metastasic setting. However, immune activation associated with immune check-point inhibitors (ICI) is not selective and a large variety of immune-related adverse events, with an increasing frequency, have been associated with anti-PD1, anti-PD-1/L-1 and anti-CTLA-4 agents. In clinical trials, and sometimes also in real life practice, patients who develop severe toxicities on ICI-based therapies are usually not allowed to resume ICI once their disease progresses, because of the chance of developing severe irAEs on rechallenge with immunotherapies. Moreover, patients with irAEs suffer important side effects due to the high dose corticosteroids that are used to treat them. Therapy with ICI is sometimes the only alternative for certain patients, and for this reason co treatment with classic (DMARDS) or biologic immunosuppression therapy and ICI must be considered. Co-treatment with this type of immunosuppressant drugs, apart from allowing the maintenance of ICI therapy, drive to a lesser use of corticosteroids, with an improvement of the safety and quality of life of the patients. Such a tailored scheme of treatment is mostly an expert opinion based on recommendation and currently there is scarce evidence supporting it. Herein we present comprehensive, current recommendations and real-world data on the use of co-treatment with ICI and DMARDS and biologic immunosuppression.

Stalled at the intersection: insurance status and disparities in post-mastectomy breast reconstruction.

PURPOSE: Post-mastectomy breast reconstruction (PMBR) is an important component of breast cancer treatment, but disparities relative to insurance status persist despite legislation targeting the issue. We aimed to study this relationship in a large health system combining a safety-net hospital and a private academic center. METHODS: Data were collected on all patients who underwent mastectomy for breast cancer from 2011 to 2019 in a private academic center and an adjacent public safety-net hospital served by the same surgical teams. Multivariable logistic regression was used to assess the effect of insurance status on PMBR, controlling for covariates that included socioeconomic, demographic, and clinical factors. RESULTS: Of 1554 patients undergoing mastectomy for breast cancer, 753 (48.5%) underwent PMBR, of which 592 (79.9%) were privately insured, 50 (6.7%) Medicare, 68 (9.2%) Medicaid, and 31 (4.2%) uninsured. Multivariable logistic regression showed a significantly higher likelihood of not undergoing PMBR for uninsured (OR 6.0, 95% CI 3.7-9.8; p < 0.0001), Medicare (OR 1.9, (95% CI 1.2-3.0; p = 0.006), and Medicaid (OR 1.5, 95% CI 1.0-2.3; p = 0.04) patients compared with privately insured patients. Age, stage, race and ethnicity, and hospital type confounded this relationship. CONCLUSION: Patients without health insurance have dramatically reduced access to PMBR compared to those with private insurance. Expanding access to this important procedure is essential to achieve greater health equity for breast cancer patients.

Is humoral and cellular response to SARS-CoV-2 vaccine modified by DMT in patients with multiple sclerosis and other autoimmune diseases?

BACKGROUND: The effect of disease-modifying therapies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response is unclear. OBJECTIVES: We aim to determine the immunological responses to SARS-CoV-2 in multiple sclerosis (MS) and anti-CD20-treated patients with other autoimmune diseases (AID). METHODS: Humoral and cellular responses we determined before and 30-90 days after vaccination in patients with MS and anti-CD20-treated patients with other AID in two Catalan centers. RESULTS: 457 patients were enrolled. Findings showed that humoral response decreased under anti-CD20s or sphingosine 1-phosphate receptor modulators (S1PRM) and with longer treatment duration and increased after 4.5 months from the last anti-CD20 infusion. Cellular response decreased in S1PRM-treated. Patients on anti-CD20 can present cellular responses even in the absence of antibodies. CONCLUSION: Anti-CD20s and S1PRM modify the immunological responses to SARS-CoV-2 vaccines.

Serum 25-hydroxy vitamin D levels in age-related macular degeneration.

BACKGROUND: The aim of this study was to determine the 25-hydroxy vitamin D (25(OH)D) levels in age-related macular degeneration (AMD) patients. METHODS: Age-related macular degeneration (AMD) patients were classified into four groups: early AMD (N = 10), intermediate AMD (N = 12), advanced atrophic AMD (N = 19) and advanced neovascular AMD (N = 52) after undergoing fundus photography. Serum 25(OH)D levels of all subjects were evaluated. From a random control group of 326 patients whose 25(OH)D levels had been measured, a group of 93 were selected to match the age range of the AMD group. We measured 25(OH)D levels during the same period to rule out seasonal variation. RESULTS: A total of 93 AMD patients (36 males and 57 females) and 93 healthy individuals (39 males and 54 females) were enrolled in this study with the mean age of 78.96 ± 8.46 vs. 78.80 ± 8.35, respectively. The patients affected by AMD had statistically significant lower 25(OH)D levels (15 ± 10 ng/mL) than the healthy subjects control group (21 ± 14 ng/mL) (p = 0.004). However, the median 25(OH)D levels in early AMD, intermediate AMD, advanced atrophic AMD and advanced neovascular AMD (12.5 ± 7.3; 15 ± 11; 15 ± 8 and 17 ± 11.5, respectively) were not statistically significant (p = 0.442). CONCLUSION: This study shows that patients affected by AMD had lower vitamin D levels compared to healthy subjects. Further research is necessary to investigate the possible association between 25(OH)D levels and AMD.

Impact of Airline Secondhand Tobacco Smoke Exposure on Respiratory Health and Lung Function Decades After Exposure Cessation.

BACKGROUND: Twenty-five percent to 45% of COPD is caused by exposures other than active smoking. Secondhand tobacco smoke (SHS) has been suggested as an independent cause of COPD, based on its association with increased respiratory symptoms and a small decrease in lung function, but its impact on respiratory health and lung function after exposure cessation has not been explored. RESEARCH QUESTION: What are the consequences of airline SHS exposure on respiratory health and lung function decades after cessation? STUDY DESIGN AND METHODS: We performed a cohort study involving flight attendants because of their exposure to SHS that stopped > 20 years ago. We included subjects ≥ 50 years of age with > 1 year vs ≤ 1 year of airline SHS exposure (ie, exposed vs unexposed). Respiratory quality of life, as determined by the St. George's Respiratory Questionnaire (SGRQ), was the primary outcome for respiratory health. Key secondary outcomes included general quality of life (the Rand Corporation modification of the 36-item Short Form Health Survey Questionnaire; RAND-36), respiratory symptoms (COPD Assessment Test; CAT), and spirometry. RESULTS: The study enrolled 183 SHS-exposed and 59 unexposed subjects. Exposed subjects were 66.7 years of age, and 90.7% were female. They were hired at 23.8 years of age, were exposed to airline SHS for 16.1 years, and stopped exposure 27.5 years before enrollment. Prior SHS exposure was associated with worsened SGRQ (6.7 units; 95% CI, 2.7-10.7; P = .001), RAND-36 physical and social function, and CAT vs unexposed subjects. SHS exposure did not affect prebronchodilator spirometry or obstruction, but was associated with lower postbronchodilator FEV1 and FEV1/FVC, total lung capacity, and diffusing capacity of the lungs for carbon monoxide in a subset of subjects. Former smoking and SHS exposure synergistically worsened SGRQ (ß = 8.4; 95% CI, 0.4-16.4; P = .04). SHS exposure in people who never smoked replicated primary results and was associated with worsened SGRQ vs unexposed people (4.7 units; 95% CI, 0.7-7.0; P = .006). INTERPRETATION: Almost three decades after exposure ended, airline SHS exposure is strongly and dose-dependently associated with worsened respiratory health, but less robustly associated with airflow abnormalities used to diagnose COPD.

Blood biomarkers recommended for diagnosing and monitoring IgG4-related disease. Considerations from the ERN ReCONNET and collaborating partners.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic, clinically heterogenous fibroinflammatory condition, characterised by an accumulation of IgG4 secreting plasma cells in affected tissues and associated with increased serum IgG4 concentrations. Despite a growing recognition of the disease among clinicians from different specialties worldwide, its indolent nature, lack of a single diagnostic test and ability to mimic other malignant, infective and inflammatory conditions, makes the diagnosis challenging. As treatment options evolve, biomarkers correlating with disease activity, predicting prognosis and response to treatment are deemed required. A multidisciplinary panel of experts from the European Reference Network for Rare and Complex Connective tissue diseases (ERN ReCONNET) and affiliated international partners have performed a narrative literature search and reviewed the current evidence of biomarkers in IgG4-RD, including immunoglobulins, cytokines, chemokines and other soluble immune mediators, and cellular components of the immune system. The aim of this paper is to provide useful information for clinicians as to the utility of biomarkers for diagnosing and monitoring IgG4-RD in clinical routine and sets out recommendations for clinical decision making.

Are Temporal Artery Biopsy Findings Related to PET/CT Findings in Giant Cell Arteritis?

BACKGROUND: Two clinical subsets of giant cell arteritis have been identified with different histological and CT findings. However, PET/CT findings have not been compared with temporal artery biopsy (TAB). OBJECTIVE: The aims of this study were to describe clinical and histological findings in patients with giant cell arteritis according to the presence or absence of aortitis in PET/CT at the disease diagnosis, and to identify independent factors related to aortic involvement. METHODS: Patients were included and followed prospectively. Clinical symptoms and TAB findings were recorded. PET/CT was performed in the first 10 days of steroid therapy. Aortitis was defined if a grade 3 uptake on visual analysis was present on arterial wall. Clinical and histological variables were compared according to the presence or absence of aortitis on PET/CT. Multivariate analysis was performed to identify independent factors related to the presence of aortitis. RESULTS: Twenty-seven patients (median age, 77.6 years) were included. PET/CT was performed with a median delay of 5.0 days. Aortitis was observed in 8 patients. Patients with aortitis were younger (69.9 vs 83.7 years, P = 0.04) and had less frequently ischemic manifestations (25.0% vs 84.2%, P = 0.006) than patients without aortitis. Giant multinucleated cells were more frequent on TAB from patients with aortitis (71.4% vs 16.7%), and its presence was an independent risk factor for the occurrence of aortic involvement on PET/CT (odds ratio, 12.2; P = 0.046). CONCLUSIONS: Our study shows that giant cells on TAB are associated with the presence of aortitis on PET/CT. Patients with aortic involvement are younger and show less frequently ischemic manifestations.

Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients.

BACKGROUND: SARS-CoV-2 infection portends a broad range of outcomes, from a majority of asymptomatic cases to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty, and co-morbidities such as obesity, diabetes, and cardiovascular disease. A precise knowledge of the molecular and biological mechanisms that may explain the association of severe disease with male sex is still lacking. Here, we analyzed the relationship of serum testosterone levels and the immune cell skewing with disease severity in male COVID-19 patients. METHODS: Biochemical and hematological parameters of admission samples in 497 hospitalized male and female COVID-19 patients, analyzed for associations with outcome and sex. Longitudinal (in-hospital course) analyses of a subcohort of 114 male patients were analyzed for associations with outcome. Longitudinal analyses of immune populations by flow cytometry in 24 male patients were studied for associations with outcome. RESULTS: We have found quantitative differences in biochemical predictors of disease outcome in male vs. female patients. Longitudinal analyses in a subcohort of male COVID-19 patients identified serum testosterone trajectories as the strongest predictor of survival (AUC of ROC = 92.8%, p < 0.0001) in these patients among all biochemical parameters studied, including single-point admission serum testosterone values. In lethal cases, longitudinal determinations of serum luteinizing hormone (LH) and androstenedione levels did not follow physiological feedback patterns. Failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and augmented circulating classical monocytes. CONCLUSIONS: Recovery or failure to reinstate testosterone levels is strongly associated with survival or death, respectively, from COVID-19 in male patients. Our data suggest an early inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed by full recovery in survivors or a peripheral failure in lethal cases. These observations are suggestive of a significant role of testosterone status in the immune responses to COVID-19 and warrant future experimental explorations of mechanistic relationships between testosterone status and SARS-CoV-2 infection outcomes, with potential prophylactic or therapeutic implications.

Serum CXCL13, BAFF, IL-21 and IL-22 levels are related to disease activity and lymphocyte profile in primary Sjögren's syndrome.

OBJECTIVES: To investigate the utility of serum BAFF, IL-17, IL-18, IL-21, IL-22, CXCL13, TNF-R2 and PD-L2 as biomarkers of disease activity in primary Sjögren's syndrome (pSS), their relationship with lymphocyte subpopulations and their accuracy to discriminate pSS from Sicca syndrome. METHODS: We conducted an observational study on 66 pSS patients and 48 controls (25 with Sicca syndrome and 23 healthy volunteers). Serum levels of BAFF, IL-17 A/F, IL-18, IL-21, IL-22, CXCL13, TNF-R2 and PD-L2 were measured using a multiplex immunoassay. Lymphocyte subpopulations were analysed by flow cytometry. Disease activity of pSS was assessed with ESSDAI at study inclusion. RESULTS: Patients with pSS presented higher serum CXCL13 (364.7 vs. 205.2 pg/mL), IL-21 (43.2 vs. 0 pg/mL) and BAFF (1646 vs. 1369 pg/mL), and lower PD-L2 levels (1950.8 vs. 2792.3 pg/mL) than controls. ESSDAI was associated with BAFF, IL-18 and IL-22. Patients with ESSDAI >0 exhibited higher CXCL13, IL-21, IL-22 and TNFR2 concentrations. IL-21 levels correlated with lower memory B-cell and higher naïve B-cell percentages and IL-22 levels correlated with increased circulating activated CD4+ T-cells. The combination of serum CXCL13, BAFF and PDL2 levels using the formula [ln(CXCL13)+ln(BAFF)]/ln(PDL2) exhibit an AUC of 0.854 (95% CI: 0.750-0.919) to discriminate between pSS and Sicca syndrome (sensitivity 77.2% and specificity 86.4% using a cut-off of 1.7). CONCLUSIONS: CXCL13, BAFF, IL-21, and IL-22 are potential biomarkers of pSS activity and IL-21 and IL-22 are associated with disturbances of lymphocyte subpopulations in pSS. The combination of serum CXCL13, BAFF, and PD-L2 levels allows discrimination between pSS and Sicca syndrome.

Neurodevelopmental Outcomes of Infants Younger Than 90 Days Old Following Enterovirus and Parechovirus Infections of the Central Nervous System.

Enteroviruses (EVs) and human parechoviruses (HPeVs) are a major cause of central nervous system (CNS) infection in young infants. They have been implicated in neurodevelopmental delay, however limited data are available. The aim of this study is to describe the clinical outcome of young infants and to assess and compare the medium-term neurodevelopment following CNS infections caused by EV and HPeV. A multicentre observational ambispective study was conducted between May 2013 and March 2018. Children under 3 months of age with EV or HPeV CNS infection excluding encephalitis were included. Infants were contacted 1 year after the acute infection and their neurological development was evaluated using the Ages and Stages Questionnaire-3 (ASQ-3). If any area assessed was abnormal during the first round of tests, a second round was completed 6 to 12 months later. Forty-eight young infants with EV and HPeV CNS infection were identified: 33 (68.8%) were positive for EV and 15 (31.3%) for HPeV. At first assessment 14 out of 29 EV (48.3%) and 3 out of 15 HPeV (20%) positive cases presented some developmental concern in the ASQ-3 test. EV-positive infants showed mild and moderate alteration in all domains analyzed and HPeV-positive infants showed mild alterations only in gross and fine motor domains. Significant alterations in communication were observed in EV-positive but not in HPeV-positive infants (31 vs. 0%, p = 0.016). At second assessment 4 out of 13 EV-positive patients (30.8%) showed mild to moderate concerns in communication and gross motor function domains and 3 out of 13 (23.1%) showed significant concern in fine motor function. Although CNS infections without associated encephalitis are generally assumed to be benign our study shows that at a median age of 18 months almost half of the EV-infected infants (48.3%) and 20% of HPeV-positive infants presented some developmental concern in the ASQ-3 test. We recommend monitor the neurological development of infants during the first years of life after HPeV CNS infection and especially after EV CNS infection, even in mild cases, for an early intervention and stimulation of psychomotor development if necessary.

Detection of Sulfate-Reducing Bacteria as an Indicator for Successful Mitigation of Sulfide Production.

Sulfate-reducing bacteria (SRBs) are one of the main sources of biogenic H2S generation in oil reservoirs. Excess H2S production in these systems leads to oil biosouring, which causes operational risks and health hazards and can increase the cost of refining crude oil. Nitrate salts are often added to the system to suppress sulfidogenesis. Because SRB populations can persist in biofilms even after nitrate treatment, identifying shifts in the sessile community is crucial for successful mitigation. However, sampling the sessile community is hampered by its inaccessibility. Here, we use the results of a long-term (148 days) ex situ experiment to identify particular sessile community members from observations of the sample waste stream. Microbial community structure was determined for 731 samples across 20 bioreactors using 16S rRNA gene sequencing. By associating microbial community structure with specific steps in the mitigation process, we could distinguish between taxa associated with H2S production and mitigation. After initiation of nitrate treatment, certain SRB populations increased in the planktonic community during critical time points, indicating the dissociation of SRBs from the biofilm. Predicted relative abundances of the dissimilatory sulfate reduction pathway also increased during the critical time points. Here, by analyzing the planktonic community structure, we describe a general method that uses high-throughput amplicon sequencing, metabolic inferences, and cell abundance data to identify successful biofilm mitigation. We anticipate that our approach is also applicable to other systems where biofilms must be mitigated but cannot be sampled easily. IMPORTANCE Microbial biofilms are commonly present in many industrial processes and can negatively impact performance and safety. Within the oil industry, subterranean biofilms cause biosouring with implications for oil quality, cost, occupational health, and the environment. Because these biofilms cannot be sampled directly, methods are needed to indirectly assess the success of mitigation measures. This study demonstrates how the planktonic microbial community can be used to assess the dissociation of sulfate-reducing bacterium (SRB)-containing biofilms. We found that an increase in the abundance of a specific SRB population in the effluent after nitrate treatment can be used as a potential indicator for the successful mitigation of biofilm-forming SRBs. Moreover, a method for determining critical time points for detecting potential indicators is suggested. This study expands our knowledge of improving mitigation strategies for biosouring and could have broader implications in other systems where biofilms lead to adverse consequences.

Naïve hepatitis B e antigen-negative chronic hepatitis B patients are at risk of carotid atherosclerosis: A prospective study.

BACKGROUND: There is an increased risk of atherosclerosis in patients with chronic hepatitis C or human immunodeficiency virus, but there is scarce data on hepatitis B virus infection. The hypothesis of this study is that hepatitis B virus infection increases the risk of carotid plaques and subclinical atherosclerosis in naïve hepatitis B e antigen (HBeAg) negative subjects. AIM: To assess the rate of carotid plaques and subclinical atherosclerosis in naïve HBeAg negative subjects in comparison with a cohort of healthy controls. METHODS: Prospective case-control collaborative study conducted in two tertiary hospitals. Four hundred and two subjects prospectively recruited at the outpatient clinic were included from May 2016 to April 2017: 201 naïve HBeAg-negative hepatitis B virus-infected [49 chronic hepatitis B (CHB) and 152 inactive carriers(ICs)] and 201 healthy controls. Anthropomorphic and metabolic measures, liver stiffness and carotid Doppler ultrasound were performed. Subclinical atherosclerosis was established on an intima-media thickness increase of ≥1.2 mm and/or the presence of carotid plaques. Normally distributed quantitative variables were compared with the Student t test and those with a non-normal distribution with the Mann-Whitney U test. Categorical variables were compared between groups using the χ 2 or Fisher exact test. RESULTS: Carotid plaques were found more often in CHB (32.7%) than ICs (17.1%) or controls (18.4%) (P = 0.048). Subclinical atherosclerosis was also increased in CHB (40.8%) vsICs (19.1%) or controls (19.4%) (P = 0.003). No differences in the risk of atherosclerosis were observed between controls and ICs. The factors independently associated with the presence of carotid plaques were age [odds ratio(OR) 1.43, P < 0.001] and CHB (OR 1.18, P = 0.004) and for subclinical atherosclerosis, age (OR 1.45, P < 0.001), CHB (OR 1.23, P < 0.001) and diabetes (OR 1.13, P = 0.028). In the subset of young subjects (< 50 years), carotid plaques (12.5% vs 1.1%, P = 0.027) and subclinical atherosclerosis (12.5% vs 2.2%, P = 0.058) were more frequent among CHB than ICs. CONCLUSION: Untreated HBeAg-negative CHB is an independent risk factor for carotid plaques and subclinical atherosclerosis, while ICs present a similar risk to controls.

Challenges Faced by Rural Primary Care Providers When Caring for COPD Patients in the Western United States.

RATIONALE: Rural chronic obstructive pulmonary disease (COPD) patients have worse outcomes and higher mortality compared with urban patients. Reasons for these disparities likely include challenges to delivery of care that have not been explored. OBJECTIVE: To determine challenges faced by rural primary care providers when caring for COPD patients. METHODS: Rural primary care providers in 7 primarily western states were asked about barriers they experienced when caring for COPD patients. RESULTS: A total of 71 rural primary care medical providers completed the survey, of which 51% were physicians and 49% were advanced practice providers (APPs). A total of 61% used Global Initiative for Chronic Obstructive Lung Disease or American Thoracic Society/European Respiratory Society guidelines as an assessment and treatment resource. The presence of multiple chronic conditions and patient failure to recognize and report symptoms were the greatest barriers to diagnose COPD. A total of 89% of providers used spirometry to diagnose COPD, but only 62% were satisfied with access to spirometry. Despite recommendations, 41% of providers never test for alpha-1 antitrypsin deficiency. A total of 87% were comfortable with their ability to assess symptoms, but only 11% used a guideline-recommended assessment tool. Although most providers were satisfied with their ability to treat symptoms and exacerbations, only 66% were content with their ability to prevent exacerbations. Fewer providers were happy with their access to pulmonologists (55%) or pulmonary rehabilitation (37%). Subgroup analyses revealed differences based on provider type (APP versus physician) and location (Colorado and Kansas versus other states), but not on population or practice size. CONCLUSIONS: Rural providers face significant challenges when caring for COPD patients that should be targeted in future interventions to improve COPD outcomes.